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,1
* PsyNuGen, INRA UMR1286, CNRS UMR5226, Université de Bordeaux 2, Bordeaux, France; and
Centre de Neurosciences Intégratives et Cognitives, Université de Bordeaux I and CNRS, Talence, France
1Correspondence: Centre de Neurosciences Intégratives et Cognitives, Université de Bordeaux I and CNRS, Bât. B2-Avenue des Facultés, 33405 Talence, France. E-mail: wim_crusio{at}yahoo.com
Xu et al. reported in The FASEB Journal on a selection study in mice allegedly implicating a polymorphic glucocorticoid receptor (GR) in inherited altered stress response and increased anxiety-type behaviors (1)
. Xu et al. carried out "divergent genetic selection for altered corticosterone response to stress" and found that the resulting two lines differed for a polymorphic glucocorticoid receptor (GRQn). They then concluded that this GR polymorphism plays a role in complex mechanisms leading to lower corticosterone response to stress.
Unfortunately, the design of this study was not only needlessly complicated, but also fundamentally flawed. As a result, this experiment does not and cannot give any conclusive results.
Xu et al. used as their start population two already established lines that had been selected for high and low heat loss (4
, 5)
. From these lines, they started a new selection experiment using a selection criterion that is not defined more precisely than "behavior, body weight, and, most important, serum corticosterone concentration (the highest or lowest in the same line, SH or SL selection, respectively) in response to restraint stress." In these experiments, the SL line is in fact the low heat loss line further selected for a low corticosterone response to restraint stress and the SH line is in fact the high heat loss line further selected for a high corticosterone response to stress. The SL and SH lines are not described or investigated further. Therefore, it cannot be excluded that the original heat-loss selected lines had already diverged for their allele frequencies for the GRQn gene. This divergence might have come to pass because of the selection for the heat-loss phenotype or because of genetic drift (2)
. In short, the results of the experiment reported by Xu et al. (1)
cannot provide any meaningful support for the hypothesis that GRQn is involved in stress regulation. The situation would have been different if a standard selection study design using bidirectional selection from a single heterogeneous start population had been used. [Even with that design, results from non-replicated studies should be interpreted with great care: due to chance and genetic drift, selected lines may differ for genes that have nothing to do whatsoever with the character selected for (2
, 3)
.]
The main question of whether the phenotypic differences measured between the SL and SH lines can be attributed, at least partly, to the glucocorticoid receptor polymorphism therefore remains unanswered. Using the present lines, the only acceptable indication of a contribution of the polyglutamine polymorphism would be the demonstration of a difference between genotypes within lines. Such an experiment is mentioned by the authors at the beginning of the discussion (p. E1808) but only as a complementary approach. By the way, a much simpler way to test the hypothesis, which does not need many years of laborious selection, would be to compare a battery of inbred strains (6)
or recombinant inbred strains (7)
for these characteristics.
There are some additional problems with this paper. These concern the fact that the polyglutamine track in the mouse glucocorticoid receptor had already been described before, the doubtful interpretation of the data in Figure 4A, and the exceptionally long series of restraint stress. However serious they may be, compared to the major flaw described above, these problems are actually rather minor.
FOOTNOTES
The opinions expressed in editorials, essays, letters to the editor, and other articles comprising the Up Front section are those of the authors and do not necessarily reflect the opinions of FASEB or its constituent societies. The FASEB Journal welcomes all points of view and many voices. We look forward to hearing these in the form of op-ed pieces and/or letters from its readers addressed to journals{at}faseb.org
REFERENCES
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